PBDs are of the general structure:
C2-substituted Compounds
In WO 2004/043963, a diverse range cytotoxic compounds having an aryl group at the C2 position, for example:
were disclosed. The synthesis of these compounds was achieved via the following intermediate:
whose synthesis was described in detail in WO 00/12508. An analagous dimeric intermediate is disclosed in WO 2010/010347.
WO 2005/085251 discloses the synthesis of a number cytoxic compounds having an aromatic substituent at C2 from the intermediate:

These intermediates are very useful for synthesis C2 substituted PBD compounds having a N10-C11 imine bond, or compounds readily derivable from these, e.g. bisulphite versions, as in WO 2010/010347. The N10 protecting groups used are not labile under the conditions used to add the C2 aryl substituents, for example, in a Suzuki coupling using a palladium catalyst.
The C2-aryl group is installed by forming a C2-enol triflate followed by a palladium catalyzed Suzuki reaction. It is advantageous to add the C2 aryl substituents as late as possible in the synthesis by the methods described above, as this means a diverse range of substituents can be added to a single ‘core’.
However, there are compounds of interest where the protecting groups or linkers desired at N10 are labile under either the triflation conditions (e.g. substituted p-aminobenzyl or p-hydroxybenzyl carbamates) or palladium catalysis (e.g. Alloc), see below.
Such groups are preferably introduced at a point in the synthesis of the PBD before the B-ring is formed by cyclisation. Otherwise, these groups would need to be added via a chloroformate to the PBD's imine bond. In addition, the cyclisation of PBD is best carried out where the pro-N10 nitrogen has only a single hydrogen attached, i.e., where the protecting group is already in place.